Innate immune responses, including natural killer (NK) cell responses, are the principal defense against viral infections prior to the development of adaptive immune responses and can play a critical role in determining the outcome of viral infection. Increasing evidence suggests that NK responses can play a significant role in control of HIV replication. However, many critical questions on the role of NK cells in the control of HIV/SIV replication remain unanswered, including the potential contribution of mucosal NK responses to virus containment. Although NK cells have been identified in both gastrointestinal and genitourinary mucosa, these cells have been relatively poorly characterized, and little is known about their role in normal hosts. Practical and ethical considerations are likely to significantly constrain efforts to elucidate the roles of mucosal NK cells in HIV-infected subjects and examination of the role of these responses in nonhuman primates is likely to offer the best opportunity to address these key questions. Recent data from our laboratory have demonstrated previously unrecognized populations of NK cells in gastrointestinal and genitourinary tissues in rhesus macaques and developed a new set of techniques to characterize NK cells in peripheral blood and mucosal tissues. Armed with these new assays and drawing on the complementary expertise of the Johnson and Haase laboratories, we propose a comprehensive set of experiments to analyze the role of NK cells in SIV-infected macaques. Specific aims include: 1. to examine the role of mucosal NK cells in modulating the course of SIV infection following vaginal challenge; 2. to examine the mechanism of recognition of SIV-infected CD4+ cells by NK cells; and 3. to carry out longitudinal studies of perturbations of KIR expression and function in NK cells from SIV-infected animals. Innate immune responses, including natural killer cells, are the first line of defense against viral infections such as HIV, and often play a key role in early containment and in shaping the immune responses that follow. Although a large number of studies suggest that natural killer cells help the body defend itself against HIV infection, almost nothing is known about natural killer cells in mucosal sites, one of the most important tissues in the body for transmission of HIV and development of AIDS. The goal of this proposal is to study the role of natural killer cells in nonhuman primates infected with simian immunodeficiency virus (SIV), with particular emphasis on studies of natural killer cells in the gut and female reproductive tract.